Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00292
Target NameAlpha-1A adrenergic receptor    
Type of TargetClinical trial target    
Drug Potency against TargetDutasteride & tamsulosinIC50 = 6 nM[1]
WAY-100135IC50 = 1490 nM[2]
ATC-0175IC50 = 300 nM[3]
SiramesineIC50 = 330 nM[4]
ISOCLOZAPINEIC50 = 64 nM[5]
ABANOQUILKi = 0.03 nM[6]
SILODOSINKi = 0.036 nM[7]
(+)-NIGULDIPINEKi = 0.16 nM[7]
SNAP-7915Ki = 0.17 nM[7]
(-)-SNAP-5089Ki = 0.18 nM[7]
MAZAPERTINEKi = 0.2 nM[8]
SNAP-6201Ki = 0.2 nM[7]
A-131701Ki = 0.22 nM[7]
RS-100329Ki = 0.25 nM[7]
WB-4101Ki = 0.35 nM[6]
L-771688Ki = 0.36 nM[7]
(-)-SNAP-5399;SNAP-5399Ki = 0.4 nM[7]
RS-17053Ki = 0.6 nM[7]
RWJ-69736Ki = 0.65 nM[7]
OCTOCLOTHEPINKi = 0.66 nM[9]
FLUANISONEKi = 0.87 nM[10]
UPIDOSINKi = 1 nM[7]
Ro-700004;RS-100975Ki = 1.3 nM[7]
SNAP-5089Ki = 1.3 nM[11]
TIOSPIRONEKi = 1.5 nM[12]
NIGULDIPINEKi = 1.8 nM[11]
SNAP-5150Ki = 1.9 nM[7]
(2-Bromo-phenyl)-(1H-imidazol-2-yl)-amineKi = 11000 nM[13]
Imidazolidin-2-ylidene-quinoxalin-6-yl-amineKi = 11000 nM[14]
MEDETOMIDINEKi = 1102 nM[15]
R-226161Ki = 125 nM[16]
SNAP-8719Ki = 1400 nM[17]
5-Bromo-8-piperazin-1-yl-imidazo[1,2-a]pyrazineKi = 1490 nM[18]
4-(3-Hydroxy-piperidin-3-yl)-benzene-1,2-diolKi = 15000 nM[19]
N-(5-Bromo-quinoxalin-6-yl)-guanidineKi = 17000 nM[14]
4-(1-Naphthalen-1-yl-vinyl)-1H-imidazoleKi = 1734 nM[20]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-oneKi = 18 nM[21]
SNAP-94847Ki = 180 nM[22]
(+/-)-nantenineKi = 2 nM[23]
A-119637Ki = 2.6 nM[7]
RWJ-68157Ki = 22 nM[7]
1-Pyridin-2-yl-piperazineKi = 2400 nM[24]
Imidazolidin-2-ylidene-o-tolyl-amineKi = 2500 nM[14]
RX-821002Ki = 27 nM[25]
CORYNANTHEINEKi = 29 nM[7]
BMY-7378Ki = 290 nM[17]
NAFTOPIDILKi = 3.7 nM[7]
8-Piperazin-1-yl-imidazo[1,2-a]pyrazineKi = 3100 nM[18]
4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolineKi = 3200 nM[26]
BP-897Ki = 33 nM[27]
SK&F-104078;SK-104078Ki = 33 nM[11]
SK&F-105854;SK-105854Ki = 3300 nM[7]
4-Benzo[b]thiophen-4-yl-1H-imidazoleKi = 343 nM[28]
sunepitronKi = 35 nM[29]
1-(2-Methoxy-phenyl)-piperazineKi = 3508 nM[30]
SK&F-104856;SK-104856Ki = 36 nM[11]
4-((E)-1-Naphthalen-1-yl-propenyl)-1H-imidazoleKi = 387 nM[20]
A-123189Ki = 4.2 nM[7]
SNAP-5036Ki = 4.4 nM[7]
1',2',3',6'-Tetrahydro-[2,4']bipyridinylKi = 4000 nM[24]
RS-513815Ki = 41 nM[7]
L-765314Ki = 420 nM[7]
SK&F-86466;SK-86466Ki = 449 nM[11]
AGN-193080Ki = 470 nM[14]
1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazineKi = 490 nM[24]
A-315456Ki = 490 nM[7]
Ro-11-04253Ki = 5 nM[7]
4-(1-Naphthalen-1-yl-ethyl)-1H-imidazoleKi = 536 nM[15]
4-(2,3-Dihydro-1H-phenalen-1-yl)-1H-imidazoleKi = 55 nM[20]
4-((Z)-1-Naphthalen-1-yl-propenyl)-1H-imidazoleKi = 57 nM[20]
4-(1-Naphthalen-1-yl-propyl)-1H-imidazoleKi = 574 nM[20]
SK&F-106686;SK-106686Ki = 58 nM[11]
2-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinolineKi = 5800 nM[26]
RWJ-68141Ki = 59 nM[7]
(2,6-Dichloro-phenyl)-(1H-imidazol-2-yl)-amineKi = 6000 nM[13]
UH-301Ki = 6080 nM[2]
4-(4-Isopropyl-morpholin-2-yl)-benzene-1,2-diolKi = 6700 nM[19]
SPIPERONEKi = 7.9 nM[7]
1-(2-Chloro-phenyl)-piperazineKi = 710 nM[30]
4-(4-Methyl-indan-1-yl)-1H-imidazoleKi = 73 nM[31]
4-Morpholin-2-yl-benzene-1,2-diolKi = 7400 nM[19]
RWJ-25730Ki = 8.2 nM[8]
AGN-192172Ki = 8900 nM[14]
RWJ-38063Ki = 9.3 nM[7]
2-(4-tert-Butyl-phenyl)-4,5-dihydro-1H-imidazoleKi = 91 nM[32]
LEVONORDEFRINKi = 9221 nM[20]
Action against Disease ModelAlfuzosinAlfuzosin significantly prolonged action potential duration (APD)(60) in rabbit Purkinje fibers (p < 0.05) and QT in isolated rabbit hearts (p < 0.05) at the clinically relevant concentration of 300 nM. In man, the QT interval corrected with Fridericia's formula increased 7.7 ms, which exceeds the 5.0-ms threshold for a positive TCQS. Effects on hK(v)11.1, hK(v)4.3, and hK(v)7.1/hKCNE1 potassi uM currents and calci uM current were not involved. At 300 nM, approximately 30x C(max), alfuzosin significantly increased whole-cell peak sodi uM (hNa(v)1.5) current (p < 0.05), increased the probability of late hNa(v)1.5 single-channel openings, and significantly shortened the slow time constant for recovery from inactivation.[33]
The Effect of Target Knockout, Knockdown or Genetic VariationsAlpha 1A-AR knockout mice: cardiac development is normal,cardiac function has decreased contraction and pressor response is decreased to PE[34]
Ref 1Prostate. 2004 Feb 1;58(2):130-44.Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. To Reference
Ref 2J Med Chem. 1997 Apr 11;40(8):1252-7.N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines: synthesis and wide range of antagonism at the human 5-HT1A receptor. To Reference
Ref 3Bioorg Med Chem Lett. 2009 Nov 1;19(21):6166-71. Epub 2009 Sep 6.Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation. To Reference
Ref 4J Med Chem. 1995 May 26;38(11):1998-2008.Sigma ligands with subnanomolar affinity and preference for the sigma 2 binding site. 1. 3-(omega-aminoalkyl)-1H-indoles. To Reference
Ref 5J Med Chem. 1997 Dec 5;40(25):4146-53.Synthesis and pharmacological evaluation of triflate-substituted analogues of clozapine: identification of a novel atypical neuroleptic. To Reference
Ref 6J Med Chem. 1995 Sep 1;38(18):3415-44.Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification. To Reference
Ref 7Bioorg Med Chem Lett. 2005 Feb 1;15(3):657-64.Pharmacophore identification of alpha(1A)-adrenoceptor antagonists. To Reference
Ref 8J Med Chem. 1994 Apr 15;37(8):1060-2.A new arylpiperazine antipsychotic with high D2/D3/5-HT1A/alpha 1A-adrenergic affinity and a low potential for extrapyramidal effects. To Reference
Ref 9J Med Chem. 2010 Oct 14;53(19):7021-34.Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for (1)-adrenoceptors. To Reference
Ref 10J Med Chem. 1987 Nov;30(11):2099-104.2-Phenylpyrroles as conformationally restricted benzamide analogues. A new class of potential antipsychotics. 1. To Reference
Ref 11J Med Chem. 1995 Sep 15;38(19):3681-716.Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. To Reference
Ref 12J Med Chem. 1996 Jan 5;39(1):143-8.3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. To Reference
Ref 13J Med Chem. 1997 Jan 3;40(1):18-23.Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists. To Reference
Ref 14Bioorg. Med. Chem. Lett. 5(15):1745-1750 (1995) To Reference
Ref 15J Med Chem. 1994 Jul 22;37(15):2328-33.A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors. To Reference
Ref 16Bioorg Med Chem. 2007 Jun 1;15(11):3649-60. Epub 2007 Mar 21.Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism. To Reference
Ref 17J Med Chem. 2005 Apr 21;48(8):3076-9.Synthesis and structure-activity relationship of fluoro analogues of 8-{2-[4-(4-methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as selective alpha(1d)-adrenergic receptor antagonists. To Reference
Ref 18J Med Chem. 1992 Oct 16;35(21):3845-57.Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines. To Reference
Ref 19J Med Chem. 1992 Mar 20;35(6):1009-18.Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors. To Reference
Ref 20J Med Chem. 1996 Jul 19;39(15):3001-13.Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine. To Reference
Ref 21J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential. To Reference
Ref 22J Med Chem. 2007 Aug 9;50(16):3883-90.Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits. To Reference
Ref 23Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. To Reference
Ref 24J Med Chem. 1984 Sep;27(9):1182-5.Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines. To Reference
Ref 25J Med Chem. 1986 Oct;29(10):2000-3.Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists. To Reference
Ref 26Bioorg Med Chem Lett. 2003 May 19;13(10):1759-62.4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists. To Reference
Ref 27J Med Chem. 2003 Aug 28;46(18):3822-39.Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands: inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors. To Reference
Ref 28J Med Chem. 2000 Mar 9;43(5):765-8.alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor. To Reference
Ref 29J Med Chem. 2006 Jun 1;49(11):3116-35.An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression. To Reference
Ref 30J Med Chem. 1991 Jun;34(6):1850-4.Pyrimido[5,4-b]indole derivatives. 1. A new class of potent and selective alpha 1 adrenoceptor ligands. To Reference
Ref 31J Med Chem. 1997 Sep 12;40(19):3014-24.Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with alpha 2-adrenoceptors involving a "methyl pocket". To Reference
Ref 32Bioorg Med Chem Lett. 2004 Sep 20;14(18):4697-9.2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands. To Reference
Ref 33J Pharmacol Exp Ther. 2008 Feb;324(2):427-33. Epub 2007 Nov 6.Alfuzosin delays cardiac repolarization by a novel mechanism. To Reference
Ref 34Life Sci. 2002 Sep 27;71(19):2207-15.Transgenic studies of alpha(1)-adrenergic receptor subtype function. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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